MEN1 promotes ferroptosis by inhibiting mTOR-SCD1 axis in pancreatic neuroendocrine tumors  

作　　者：Zeng Ye Haidi Chen Shunrong Ji Yuheng Hu Xin Lou Wuhu Zhang Desheng Jing Guixiong Fan Yue Zhang Xuemin Chen Qifeng Zhuo Jie Chen Xiaowu Xu Xianjun Yu Jin Xu Yi Qin Heli Gao 

机构地区：[1]Center for Neuroendocrine Tumors,Fudan University Shanghai Cancer Center,Shanghai 200032,China [2]Department of Pancreatic Surgery,Fudan University Shanghai Cancer Center,Shanghai 200032,China [3]Department of Oncology,Shanghai Medical College,Fudan University,Shanghai 200032,China [4]Shanghai Pancreatic Cancer Institute,Shanghai 200032,China [5]Pancreatic Cancer Institute,Fudan University,Shanghai 200032,China [6]Department of Hepatobiliary and Pancreatic Surgery,The Third Affiliated Hospital of Soochow University,Changzhou 213003,China

出　　处：《Acta Biochimica et Biophysica Sinica》2022年第11期1599-1609,共11页生物化学与生物物理学报（英文版）

基　　金：This work was supported by the grants from the National Natural Science Foundation of China(Nos.82141129,82173281,82173282,82172577,82172948,81972725,81972250,U21A20374,and 81871950);Science and Technology Commission of Shanghai Municipality(No.20ZR1471100);Shanghai Municipal Science and Technology Major Project(No.21JC1401500);Scientific Innovation Project of Shanghai Education Committee(No.2019-01-07-00-07-E00057);Clinical Research Plan of Shanghai Hospital Development Center(No.SHDC2020CR1006A);Xuhui District Artificial Intelligence Medical Hospital Cooperation Project(No.2021-011),Commission of Health and Family Planning(No.2018YQ06);Shanghai Municipal Science and Technology Commission(No.19QA1402100)。

摘　　要：Pancreatic neuroendocrine tumor(pNET)is the second most common malignant tumors of the pancreas.Multiple endocrine neoplasia 1(MEN1)is the most frequently mutated gene in pNETs and MEN1-encoded protein,menin,is a scaffold protein that interacts with transcription factors and chromatin-modifying proteins to regulate various signaling pathways.However,the role of MEN1 in lipid metabolism has not been studied in pNETs.In this study,we perform targeted metabolomics analysis and find that MEN1 promotes the generation and oxidation of polyunsaturated fat acids(PUFAs).Meanwhile lipid peroxidation is a hallmark of ferroptosis,and we confirm that MEN1 promotes ferroptosis by inhibiting the activation of mTOR signaling which is the central hub of metabolism.We show that stearoyl-coA desaturase(SCD1)is the downstream of MEN1-mTOR signaling and oleic acid(OA),a metabolite of SCD1,recues the lipid peroxidation caused by MEN1 overexpression.The negative correlation between MEN1 and SCD1 is further verified in clinical specimens.Furthermore,we find that BON-1 and QGP-1 cells with MEN1 overexpression are more sensitive to everolimus,a widely used drug in pNETs that targets mTOR signaling.In addition,combined use everolimus with ferroptosis inducer,RSL3,possesses a more powerful ability to kill cells,which may provide a new strategy for the comprehensive therapy of pNETs.

关 键 词：pancreatic neuroendocrine tumor MEN1 ferroptosis mTOR signaling SCD1 

分 类 号：R735.9[医药卫生—肿瘤]